Heavy metal salts, particularly zinc salts of 2-mercaptopyridine-1-oxides have long been of interest as anti-bacterial agents. The zinc salt of 2-mercaptopyridine-N-oxide has found particular use in shampoos as an anti-dandruff agent.
Because of the utility of 2-mercaptopyridine-1-oxide and ring-substituted derivitives thereof, there has been a demand for a synthesis thereof which gives good yields of pure product, and which is generally applicable to the class of 2-mercaptopyridine-1-oxides. 2-Aminopyridine and ring-substituted derivitives thereof are generally cheap and readily available commercially. It is therefore an object of this invention to provide a process of manufacture for 2-mercaptopyridine-1-oxide and ring-substituted derivitives thereof, using 2-aminopyridine or ring-substituted derivitives thereof as the starting material. It is a further object of this invention to provide a process of manufacture, yielding the desired compounds, in high overall yield, with a minimum of purification. It is a further object of this invention to provide such a process of manufacture which requires little or no isolation of intermediates between the starting material and the final product.
The object of this invention has been realized by a process of manufacture, following the reaction scheme outlined below: ##STR1## where X is Cl or Br, Y is Cl, Br, HSO.sub.4, or BF.sub.4,
R.sup.1, r.sup.2, r.sup.3 and R.sup.4 are hydrogen, fluorine, chlorine, bromine, nitro, C.sub.1 to C.sub.12 -alkyl, C.sub.1 to C.sub.4 -alkoxy, benzyl, phenyl or phenoxy, provided at least two of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are hydrogen.
The process includes the steps of diazotizing a 2-aminopyridine-1-oxide salt in dilute hydrochloric acid, and treating the resulting diazonium salt with hydrochloric acid or hydrobromic acid to give the corresponding 2-chloro-or 2-bromo-pyridine-1-oxide as the corresponding hydrohalide salt, followed by treatment with a sulfhydryl donor to give the corresponding 2-mercaptopyridine-1-oxide.
The acetylating agent of step (1) is preferably acetic anhydride. Of course, other loweralkanoyl acylating agents can be used in place of acetylating agents, for instance, propionic anhydride, but acetylation is preferred as a matter of economics and ease.
The oxidation of step (2) can be carried out with any of the known peroxidizing agents such as peracetic acid or hydrogen peroxide. For instance, 40% peracetic acid in an inert solvent such as acetic acid, chloroform, dichloroethane, trichlorothane, tetrachloroethane, chlorobenzene, dichlorobenzene, toluene or xylene, is quite effective. The peroxidation can also be carried out in a two-phase system with 30-60% aqueous hydrogen peroxide and an inert solvent such as the water-insoluble oils just named. Alternatively, 30-60% aqueous hydrogen peroxide can be used in a one-phase system with acetic acid as the solvent. The preferred agent and solvent for step (2) is 40% peracetic acid in xylene.
The acetyl-cleavage of step (3) is readily carried out with aqueous mineral acid, such as sulfuric acid, hydrobromic acid or hydrochloric acid. For an easy diazotization and replacement of the diazonium group in the next step, (4), hydrochloric acid is preferred. Furthermore, if it is desired to proceed directly to step (4), without isolation of compound III, hydrochloric acid would be further preferred in step (3), because it is also preferred in step (4).
The diazotization of step (4) is carried out under stronger acidic conditions than are commonly encountered in standard diazotization methods. The diazotization is effected with sodium nitrite and strong acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or tetrafluoroboric acid, especially hydrochloric acid in strong concentration or a mixture of hydrochloric acid and tetrafluoroboric acid. When hydrobromic acid is used, bromine must be added, as taught by Lyman C. Craig, Journal of Americal Chemical Society, 56, 231 (1934). The resulting diazonium salt is then treated, in the second part of step (4), with hot hydrochloric or hydrobromic acid to give compound II where X is chlorine or bromine. Hydrochloric acid is preferred as is compound II where X is chlorine. The artisan will appreciate that other equivalents to sodium nitrite-hydrochloric acid may be used, such as nitrosylchloride in hydrochloric acid, or ammonium nitrite in hydrochloric acid.
In step (5), the replacement of the 2-chloro or 2-bromo group with a mercapto group can be effected by a sulfhydryl donor. By sulfhydryl donor is meant agents which generate actually, or in effect, sulfhydryl ions. Eligible sulfhydryl donors include alkali metal polysulfides, alkali metal sulfides, alkali metal hydrosulfides, thiourea, thioacetic acid, alkali metal trithiocarbonates, alkali metal thiosulfates and alkali metal thiophosphates. Among the alkali metals, sodium is preferred. Of the described sulfhydryl donors, sodium hydrosulfide and thiourea are preferred.
Methods of preparing heavy metal double salts of 2-mercaptopyridine-N-oxides are taught in the art, for instance, U.S. Pat. No. 2,809,971, which issued on Oct. 15, 1957, on the application of Jack Bernstein and Kathryn A. Loose.